Opioid microinjection into raphe magnus modulates cardiorespiratory function in mice and rats

Am J Physiol Regul Integr Comp Physiol. 2009 Nov;297(5):R1400-8. doi: 10.1152/ajpregu.00140.2009. Epub 2009 Aug 26.


The raphe magnus (RM) participates in opioid analgesia and contains pain-modulatory neurons with respiration-related discharge. Here, we asked whether RM contributes to respiratory depression, the most prevalent lethal effect of opioids. To investigate whether opioidergic transmission in RM produces respiratory depression, we microinjected a mu-opioid receptor agonist, DAMGO, or morphine into the RM of awake rodents. In mice, opioid microinjection produced sustained decreases in respiratory rate (170 to 120 breaths/min), as well as heart rate (520 to 400 beats/min). Respiratory sinus arrhythmia, indicative of enhanced parasympathetic activity, was prevalent in mice receiving DAMGO microinjection. We performed similar experiments in rats but observed no changes in breathing rate or heart rate. Both rats and mice experienced significantly more episodes of bradypnea, indicative of impaired respiratory drive, after opioid microinjection. During spontaneous arousals, rats showed less tachycardia after opioid microinjection than before microinjection, suggestive of an attenuated sympathetic tone. Thus, activation of opioidergic signaling within RM produces effects beyond analgesia, including the unwanted destabilization of cardiorespiratory function. These adverse effects on homeostasis consequent to opioid microinjection imply a role for RM in regulating the balance of sympathetic and parasympathetic tone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Arrhythmia, Sinus / chemically induced
  • Arrhythmia, Sinus / physiopathology
  • Bradycardia / chemically induced
  • Bradycardia / physiopathology
  • Cardiovascular System / drug effects*
  • Cardiovascular System / physiopathology
  • Disease Models, Animal
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / administration & dosage
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / adverse effects
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology*
  • Heart Rate / drug effects
  • Heart Rate / physiology
  • Homeostasis / drug effects
  • Homeostasis / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microinjections
  • Morphine / administration & dosage
  • Morphine / adverse effects
  • Morphine / pharmacology*
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Raphe Nuclei / drug effects*
  • Raphe Nuclei / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Insufficiency / chemically induced
  • Respiratory Insufficiency / physiopathology
  • Respiratory System / drug effects*
  • Respiratory System / physiopathology
  • Sleep / drug effects
  • Sleep / physiology


  • Analgesics, Opioid
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Morphine